Process for the preparation of clopidogrel

ABSTRACT

A process for the preparation of clopidogrel (1) 
     
       
         
         
             
             
         
       
         
         
           
             by reaction of the N,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane (12) 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             with (R)-2-chlorophenylacetic acid derivatives of formula (13) 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             in which X and R have the meanings as indicated in the disclosure.

The present invention relates to antiplatelet and antithrombotic agents,more particularly to a process for the preparation of clopidrogrel (1):methyl[(S)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]-pyridyl)acetate.

PRIOR ART

Clopidogrel (1) is a compound having antiplatelet and antithromboticactivities first described by Aubert et al. (EP 0 099 802 and U.S. Pat.No. 4,529,596) and synthesized by reaction between4,5,6,7-tetrahydro[2,3-c]thienopyridine (2) and2-chloro-2-(2′-chlorophenyl)acetic acid methyl ester (3) (scheme 1).

According to this process, the product is obtained as a racemic mixture.The separation of the two enantiomers can be carried out with opticalresolution procedures as disclosed in EP 0281 459, but this involves aremarkable decrease in yields.

A method overcoming said drawback has been suggested in WO 98/51689, inwhich clopidrogrel is prepared by reacting 2-(2-thienyl)-ethylamine (4)with o-chlorobenzaldehyde (5) and sodium cyanide. The resulting nitrile(6) is transformed into the corresponding amide (7) and subsequentlyinto the methyl ester (8). Intermediate (8) in the configurationsuitable for the synthesis of clopidogrel, can be prepared by opticalseparation of the amide (7) or the ester (8) with optically activeacids. Finally, the desired enantiomer of ester (8) is cyclized withformaldehyde in acid medium to give clopidogrel.

Alternatively, as disclosed in EP 466569, intermediate (8) can beobtained by reacting methyl 2-amino-(2-chlorophenyl)acetate (9) with a2-(2-thienyl)ethanol derivative (10), in which X is halogen or asulfonic group (scheme 3)

or by reacting a methyl 2-halo-(2-chlorophenyl)acetate, for examplecompound (3), with 2-(2-thienyl)ethylamine (4).

Finally, WO 99/18110 discloses the preparation of clopidogrel byreacting tetrahydrothieno pyridine (2) with (R)-2-chloro mandelic acidsulfonic esters (11).

However, this method still has the disadvantage of using tetrahydrothieno pyridine, which is a low-melting solid hardly obtainable in thepure form.

DETAILED DISCLOSURE OF THE INVENTION

It has now been found that clopidogrel (1), or a pharmaceuticallyacceptable salt thereof, can be prepared by reactingN,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane (12)

with a (R)-2-chlorophenylacetic acid derivative of formula (13)

wherein:

-   -   R is a hydrogen atom or a straight or branched C₁-C₄ alkyl        group, and X is:        -   a halogen selected from fluorine, chlorine, bromine and            iodine, preferably bromine or chlorine;        -   a OSO₂R¹ group wherein R¹ is a straight or branched C₁-C₄            alkyl group, optionally substituted with one or more halogen            atoms, a straight or branched C₁-C₈ perfluoroalkyl group, an            aromatic ring optionally substituted with one or more            halogen atoms, straight or branched C₁-C₄ alkyl groups, or            nitro groups;        -   a OCOR₁ ester group in which R¹ has the meanings defined            above;        -   a —ONO₂ group;        -   a OP(OR)₂ phosphite group or a OPO(OR)₂ phosphate group, in            which R has the meaning as defined above; and, if desired,            salifying a compound of formula (I).

When R¹ is a substituted alkyl group or aromatic ring, it is preferablysubstituted by 1 to 3 substituents as defined above, which may be thesame or different.

Preferred compounds of formula (13) are(R)-2-(2-chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)acetic acid methylester (13a) and (R)-2-bromo-2-(2-chlorophenyl)acetic acid methyl ester(13b).

The process for the preparation of clopidogrel according to the presentinvention is carried out in the presence of a protic or aprotic organicsolvent and, if the case, in the presence of an organic or inorganicbasic agent.

More particularly, a compound of formula (13) is added to a solution orsuspension of intermediate (12) in a suitable organic solvent. Theprotic or aprotic organic solvent is, for instance, selected from aketone, preferably acetone, methyl ethyl ketone and methyl isobutylketone, an alcohol, preferably a C1-C4 alkanol, acetonitrile, anaromatic hydrocarbon, preferably toluene, xylene and a chlorinatedsolvent, preferably methylene chloride, or a mixture thereof. Accordingto a preferred embodiment of the invention, the solvent is acetone,acetonitrile or methanol. Compound of formula (12) is used in molarratios ranging from 0.5:1 to 3:1 with respect to intermediate of formula(13), preferably ranging from 1:1 to 2:1.

When the reaction is carried out in the presence of an organic basicagent, such agent can be preferably selected from a compound of formula(12) itself, i.e. N,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridylmethane, diisopropyl-ethyl-amine, 4-(dimethylamino)pyridine,triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and1,4-diazabicyclo[2.2.2]octane. An inorganic basic agent is preferably analkali, or alkaline-earth metal carbonate, e.g. potassium carbonate. Thebase can be used in molar ratios ranging from 0.5:1 to 1.5:1 withrespect to compound (13), preferably in stoichiometric ratio. Thereaction is carried out at a temperature ranging from 0° C. to thereflux temperature of the solvent, preferably from 20 to 70° C. Aftercompletion of the reaction the mixture is cooled at room temperaturethen, after the appropriate work up, the resulting crude is dissolved inacetone to give a solution from which clopidogrel can be precipitated asa salt by addition of a pharmacologically acceptable acid, for exampleconcentrated sulfuric acid to afford clopidogrel hemisulfate.

Aminal N,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane offormula (12) is a novel compound and is also an object of the presentinvention. This compound is obtained by reacting commercially available2-(2-thienyl)ethylamine (4) with aqueous formaldehyde orparaformaldehyde or trioxane in a medium acidified by organic or mineralacids (scheme 5).

The organic acid is preferably selected from formic, acetic,trichloroacetic, trifluoroacetic, methanesulfonic, p-toluenesulfonicacids, more preferably is formic acid. A preferred mineral acid ishydrochloric acid.

When the reaction is carried out in the presence of an organic acid,this can be used as the solvent.

When the reaction is carried out in the presence of a mineral acid,water is used as the solvent. The mineral acid is usually employed in astoichiometric amount or in excess, the mineral acid:2-(2-thienyl)ethyl-amine (4) molar ratio preferably ranging from 1:1 to3:1.

Formaldehyde in the form of 37% aqueous solution, paraformaldehyde ortrioxane, is usually employed in molar ratios ranging from 1:1 to 1:3with respect to 2-thienyl-ethylamine (4), preferably in a 1:1.5 ratio.

The reaction is carried out at a temperature ranging from 0° C. to thereflux temperature of the reaction mixture, preferably from 10 to 60° C.

When the reaction is completed, the acid is distilled off under vacuumor is preferably transformed into the corresponding salt by addition ofa base. Preferred bases are sodium hydroxide, potassium hydroxide orammonium hydroxide. After basifying, e.g. with an alkali metalhydroxide, intermediate (12) is recovered by filtration or extractionwith suitable organic solvents. The solvent used for the extraction ofintermediate (12) is preferably an aromatic hydrocarbon, more preferablytoluene or xylene, or a chlorinated solvent, more preferably methylenechloride.

After removing the solvent used for the extraction, intermediate (12) ispurified by crystallization from a suitable solvent. The solvent usedfor the crystallization of intermediate (12) can be selected from aketone, preferably acetone and methyl isobutyl ketone, an ester,preferably ethyl acetate and butyl acetate and an alcohol, preferablymethanol, ethanol and isopropanol.

An advantageous aspect of the present invention over the methods using4,5,6,7-tetrahydro[3,2-c]thienopyridine (2), which is a low-meltingsolid, very soluble in the organic solvents and therefore difficult topurify by crystallization, is that compound (12) is solid and can becrystallized. Furthermore, no by-products are formed during thepreparation of compound (12), conversely, following the syntheticprocedures described in literature for4,5,6,7-tetrahydro[3,2-c]thienopyridine (2), by-products form which haveto be removed before carrying out the process for the preparation ofclopidogrel.

The invention is illustrated in greater detail by the followingexamples.

EXAMPLES

Methyl (R)-2-(2-Chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)acetate (13a)is prepared according to the procedure disclosed in WO 99/18110.

Example 1 Preparation of N,N″-bis-4,5,6,7-tetrahydro[3,2-c]thienopyridylmethane (12)

Method 1

2440 g of anhydrous formic acid (53.04 moles) are placed in a 3 lround-bottom flask, equipped with mechanical stirrer, thermometer anddropping funnel. 500 g of 2-(2-thienyl)ethylamine (4) (3.94 moles) arethen slowly added thereto, while allowing temperature to reach 40° C.The resulting solution is cooled at room temperature, then 186.5 g of95% paraformaldehyde (5.91 moles) are added in 10 minutes. After 14hours at room temperature, the resulting solution is slowly poured into6660 g of a 30% w/w sodium hydroxide solution (50 moles), while keepingtemperature below 30° C. The resulting suspension is kept under stirringat room temperature for 2 hours, then the precipitated solid isrecovered by filtration, washed with water and taken up into 550 ml ofmethanol. The obtained suspension is stirred at room temperature for 2hours, then the solid is filtered, washed with methanol and dried undervacuum at 45° C., thereby obtaining 462 g (1.59 moles; yield: 81%) ofN,N″-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane (12) as awhite crystalline solid.

¹H-NMR (CDCl₃, δ in ppm): 2.90 (m, 8H), 3.36 (s, 2H), 3.66 (s, 4H), 6.74(d, 2H), 7.08 (d, 2H) m.p.=126.3° C.

Method 2

50 g of 2-(2-thienyl)ethylamine (4) (0.394 moles) and 250 ml of waterare placed in a 500 ml round-bottom flask equipped with mechanicalstirrer, thermometer and dropping funnel. 48 g of a 36% w/w hydrochloricacid aqueous solution (0.473 moles) are then slowly added and theresulting solution is heated to 50° C., then added with 47.9 g of a 37%w/w formaldehyde aqueous solution (0.591 moles) in about 20 minutes.After 5 hours at 50° C., the resulting mixture is cooled at roomtemperature, neutralized with 20.8 g of sodium hydroxide scales (0.52moles) and subsequently extracted with 130 ml of toluene. The resultingorganic phase is washed twice with 50 ml of water, then concentrated toa residue under reduced pressure and the resulting mixture is taken upwith 100 ml of acetone, to obtain a suspension which is kept understirring for two hours. The formed precipitate is filtered with suctionand washed with acetone, thereby obtaining 26 g ofN,N″-bis-4,5,6,7-tetrahydro-[3,2-c]thienopyridyl methane (12) (89.7mmoles, yield: 45.5%) as a white solid.

Example 2 Preparation of methyl(S)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]5-pyridyl)acetate(1)

Method 1

31.6 g (0.108 moles) of N,N″-bis-4,5,6,7-tetrahydro[3,2-c]-thienopyridylmethane (12) and 150 ml of acetonitrile are placed in a 500 mlthree-necked round-bottom flask equipped with magnetic stirrer,condenser and dropping funnel. The resulting suspension is kept undernitrogen atmosphere and then refluxed. A solution consisting of 40 g(0.104 moles) of methyl(R)-2-(2-chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)acetate (13a)dissolved in 150 ml of acetonitrile is then added in 1 hour 30 minutes.1 Hr after the end of the addition, the mixture is cooled to −15° C. andthe precipitated solid is filtered. The resulting clear solution isanalyzed by HPLC (HPLC yield: 74%). The solvent is evaporated off underreduced pressure and the residue is taken up in toluene (about 600 ml)and treated with a 5% w/w sodium bicarbonate aqueous solution (100 ml).The organic phase is washed with 100 ml of water and filtered throughdecolourizing charcoal. The solvent is then removed under reducedpressure and the residue is taken up into 300 ml of acetone. Theresulting clear solution is added with concentrated sulfuric acid toacid pH, while keeping temperature at 20° C. The mixture is stirred atroom temperature for 12 hours, then the precipitated solid is recoveredby filtration and washed with fresh acetone, thereby obtaining 23.92 gof clopidogrel hemisulfate (57.02 mmoles, yield=55%), which isidentified by comparison.

Method 2

7.51 g (25.9 mmoles) ofN,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane (12), 30 ml ofacetonitrile and 3.57 g (25.9 mmol) of potassium carbonate are placed ina 250 ml three-necked round-bottom flask equipped with magnetic stirrer,condenser and dropping funnel. The resulting suspension is kept undernitrogen atmosphere and refluxed, then added with a solution consistingof 20 g (51.8 mmoles) of compound (13a) dissolved in 70 ml ofacetonitrile, in 4 hours. 16 Hrs after the end of the addition, themixture is cooled at room temperature, then after 1 hour the solid isfiltered. According to HPLC analysis, the resulting clear solutioncontains g 7.5 of clopidogrel base (yield: 45%). The resulting productis then recovered as hemisulfate following the procedure described inMethod 1.

Method 3

2.75 g (9.48 mmoles) of N,N′-bis-4,5,6,7-tetrahydro[3,2-c]-thienopyridylmethane (12) and 8 ml of acetonitrile are placed in a 25 ml three-neckedround-bottom flask equipped with magnetic stirrer, condenser anddropping funnel. The resulting suspension is kept under nitrogenatmosphere and refluxed, then added with a solution consisting of 2.5 g(9.48 mmoles) of methyl (R)-2-bromo-(2-chlorophenyl)acetate (13b)dissolved in 8 ml of acetonitrile, in 1 hour 30 minutes. 2 Hrs 30minutes after the end of the addition, the mixture is cooled at roomtemperature and the precipitated solid is filtered off. According toHPLC analysis, the resulting clear solution contains 1.95 g ofclopidogrel base (yield: 64%). The resulting product is then recoveredas hemisulfate following the procedure described in Method 1.

Method 4

3.76 g (12.97 mmoles) of N,N′-bis-4,5,6,7-tetrahydro[3,2-c]thienopyridylmethane (12) and 11 ml of acetone are placed in a 50 ml three-neckedround-bottom flask equipped with magnetic stirrer and dropping funnel.The resulting suspension is added with a solution consisting of 2.5 g(6.48 mmoles) of compound (13a) in 9 ml of acetone in 40 minutes. 25 Hrsafter the end of the addition, the precipitated solid is filtered off.According to HPLC analysis, the resulting clear solution contains 1.81 gof clopidogrel base (yield: 87%). The solvent is evaporated off underreduced pressure, the residue is taken up with toluene (30 ml) and theresulting solution is treated with decolorizing charcoal. The obtainedclear solution is added with water (20 ml) and acetic acid to pH 3-4.The organic phase is separated, washed with water (20 ml) andconcentrated to a residue under reduced pressure. The resulting oil istaken up into acetone, then clopidogrel (1) is isolated as hemisulfatefollowing the procedure described in Method 1.

Method 5

3.76 g (12.97 mmoles) ofN,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane (12) and 11 mlof acetone are placed in a 50 ml three-necked round-bottom equipped withmagnetic stirrer, condenser and dropping funnel. The resultingsuspension is refluxed while adding a solution consisting of 2.5 g (6.48mmoles) of compound (13a) in 9 ml of acetone in 40 minutes. 2 Hrs afterthe end of the addition, the reaction mixture is cooled at roomtemperature, and the precipitated solid is filtered off after 1 hour.According to HPLC analysis, the resulting clear solution contains g 1.75g of clopidogrel base (yield: 84%). Clopidogrel (1) is then isolated ashemisulfate following the procedure described in Method 4.

Method 6

1.88 g (6.48 mmoles) ofN,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane (12), 11 ml ofacetone and 0.84 g (6.48 mmol) of diisopropyl-ethyl-amine are placed ina 50 ml three-necked round-bottom equipped with magnetic stirrer,condenser and dropping funnel. The resulting mixture is refluxed whileadding a solution consisting of 2.5 g (6.48 mmoles) of compound (13a) in9 ml of acetone in 40 minutes. The resulting mixture is refluxed untilcompletion of the reaction, then cooled at room temperature. Accordingto HPLC analysis, the resulting clear solution contains 1.35 g ofclopidogrel base (yield: 65%). The resulting product is then isolated ashemisulfate following the procedure described in Method 4.

Method 7

3.76 g (12.97 mmoles) of N,N′-bis-4,5,6,7-tetrahydro[3,2-c]thienopyridylmethane (12), 20 ml of methanol and 2.5 g (6.48 mmoles) of compound(13a) are placed in a 50 ml three-necked round-bottom flask equippedwith magnetic stirrer, condenser and dropping funnel. The resultingsuspension is refluxed for 1 hour 30 minutes. The resulting mixture iscooled at room temperature and kept at this temperature for 1 hour. Theformed solid is filtered off. According to HPLC analysis, the resultingclear solution contains 1.65 g of clopidogrel base (yield 79%).Clopidogrel is then isolated as hemisulfate following the proceduredescribed in Method 4.

1. A process for the preparation of methyl[(S)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetate] (1), or a pharmaceutically acceptable saltthereof,

wherein said process comprises, reactingN,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane (12)

with a (R)-2-chlorophenylacetic acid derivative of formula (13)

wherein: R is a hydrogen atom or a straight or branched C₁-C₄ alkylgroup, and X is: a halogen selected from fluorine, chlorine, bromine andiodine; a OSO₂R¹ group wherein R¹ is a straight or branched C₁-C₄ alkylgroup, optionally substituted with one or more halogen atoms, a straightor branched C₁-C₈ perfluoroalkyl group, an aromatic ring optionallysubstituted with one or more halogen atoms, straight or branched C₁-C₄alkyl groups, or nitro groups; a OCOR¹ ester group in which R¹ has themeanings defined above; a —ONO₂ group; a OP(OR)₂ phosphite group or aOPO(OR)₂ phosphate group, in which R has the meaning as defined above;and, if desired, salifying a compound of formula (I).
 2. The process asclaimed in claim 1 wherein a compound of formula (13) is selected fromthe group consisting of(R)-2-(2-chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)acetic acid methylester and (R)-2-bromo-2-(2-chlorophenyl)acetic acid methyl ester.
 3. Theprocess as claimed in claim 1 wherein the reaction is carried out in aprotic or aprotic organic solvent, and, if the case, in the presence ofa basic agent.
 4. The process as claimed in claim 1 wherein the molarratio of compound of formula (12) to intermediate of formula (13) rangesfrom 0.5:1 to 3:1.
 5. The process as claimed in claim 3 wherein theorganic solvent is selected from the group consisting of a ketone, analcohol, acetonitrile, an aromatic hydrocarbon and a chlorinatedsolvent.
 6. The process as claimed in claim 3 wherein the basic agent isan organic base selected from the group consisting ofN,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane,diisopropyl-ethyl-amine, 4-(dimethylamino)pyridine, triethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo [2.2.2]octane.7. The process as claimed in claim 5 wherein the organic base isN,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridyl methane.
 8. Theprocess as claimed in claim 3 wherein the basic agent is an inorganicbase selected from the group consisting of an alkali and alkaline-earthmetal carbonate.
 9. The process as claimed in claim 1 wherein thereaction temperature ranges from 0° C. to the reflux temperature of thesolvent.
 10. Compound N,N′-bis-4,5,6,7-tetrahydro-[3,2-c]-thienopyridylmethane (12)